One example of an antithrombosis approach is a method that inhibits the enzyme activity of thrombin. Compounds having an antagonistic effect on thrombin receptors are recently anticipated to exert a prominent effect in the treatment and prevention of diseases in which thrombin is involved, for example, thrombosis, vascular restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart diseases, disseminated intravascular coagulation syndrome, hypertension, inflammatory diseases, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological disorders, and malignant tumors. Therefore, thrombin receptor antagonists that satisfy points such as pharmacological activity, specificity for thrombin receptors, safety, dose, and oral effectiveness were needed.
2-Iminopyrrolidine derivatives and salts thereof have already been found to have a prominent inhibitory activity on thrombin receptors and to be useful as thrombin receptor antagonists (Patent Document 1: WO 02/085855). Among the 2-iminopyrrolidine derivatives and salts thereof, Patent Document 1 describes methods for producing, for example, compounds having the following formula (A1):
(wherein RA represents a C1-6 alkyl group, RB represents a C1-6 alkoxy group, and RC represents a 5-14 membered heterocyclic group), or salts thereof.
Furthermore, Patent Document 1 above describes that an isoindole-containing derivative (A2) having the following formula may be an important intermediate in the production of the aforementioned A1 compounds, and describes a method for producing the isoindole derivative (A2), wherein 4,5-diethoxy-3-fluorophthalonitrile (A3) as shown below is dissolved in ethyl acetate-ethanol-methanol and reacted after addition of platinum oxide (Step 4 and such in Example 7 of Patent Document 1). (Unless otherwise specified, “Et” represents an ethyl group in the present description.)
[Patent Document 1] WO 02/085855.